Methods and kits for diagnosing, prognosing and monitoring parkinson's disease
Inventors
POTASHKIN, Judith Ann • SANTIAGO, Jose Alfredo
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-9970056-B2
Publication Date
2018-05-15
Expiration Date
2035-09-30
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Abstract
Network-based meta-analysis of four independent microarray studies identified the hepatocyte nuclear factor (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene upregulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most downregulated gene. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during 3 years follow up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.
Core Innovation
The invention provides methods and kits for diagnosing, prognosing, and monitoring Parkinson's Disease (PD) in human subjects by assessing gene expression levels in blood samples. It focuses on the measurement of specific gene expression, particularly the upregulation of HNF4A and downregulation of PTBP1, which were identified as central regulatory hub genes through network-based meta-analysis of multiple blood microarray datasets from PD patients.
The diagnosis involves obtaining a blood sample from a person suspected of having PD, determining the expression level of at least one gene from a defined set, and comparing these levels to those found in healthy controls. Increased expression of certain genes (e.g., HNF4A) and decreased expression of others (e.g., PTBP1) serve as molecular signatures indicative of PD. This dual-biomarker approach achieved 90% sensitivity and 80% specificity in distinguishing PD patients from healthy controls and allows tracking of disease progression over time.
The core problem addressed is the lack of reliable, accessible biomarkers for early detection and progression monitoring of PD, which has historically required clinical assessment and neurological examination rather than objective laboratory measures. By identifying dynamic gene expression changes in blood, the invention facilitates earlier diagnosis and improved monitoring of therapeutic interventions in PD patients.
Claims Coverage
There are three main inventive features described in the independent claims.
Method for diagnosing, prognosing or monitoring Parkinson's disease using HNF4A and PTBP1 expression levels in blood
This method involves: 1. Obtaining a blood sample from a human subject suspected of having PD. 2. Determining the expression level of both HNF4A and PTBP1 in the sample using specific primer pairs (HNF4A with SEQ ID NO:03 and 04; PTBP1 with SEQ ID NO:05 and 06). 3. Comparing these expression levels to those in a non-PD, healthy control sample. An increased expression of HNF4A and a decreased expression of PTBP1 in the patient's sample compared to the control is indicative of PD, enabling diagnosis.
Method of treating Parkinson's disease based on diagnosis using HNF4A and PTBP1 expression levels
This method includes: 1. Diagnosing a human subject as having PD through measurement of HNF4A and PTBP1 expression in a blood sample, as described above, using the specific primer pairs. 2. Comparing the expression levels to those from a healthy control to confirm diagnosis. 3. Administering a PD treatment regimen to the diagnosed subject. The inventive feature is the linkage of diagnosis using these molecular biomarkers directly to subsequent treatment.
Diagnostic, prognostic, or monitoring kit for Parkinson's disease containing primer pairs for HNF4A and PTBP1
This kit consists of: - A set of primer pairs suitable for detecting and quantifying the nucleic acid expression of HNF4A (SEQ ID NO:03 and 04). - A set of primer pairs suitable for detecting and quantifying the nucleic acid expression of PTBP1 (SEQ ID NO:05 and 06). The kit enables users to determine mRNA levels of these genes in blood samples for diagnosis, prognosis, or monitoring of PD.
The claims are primarily directed to molecular diagnostic and monitoring methods for PD using the combined measurement of HNF4A and PTBP1 expression levels in blood, to methods of treatment that leverage this diagnosis, and to specialized kits containing the necessary primers for these applications.
Stated Advantages
Provides a reliable blood-based diagnostic and prognostic biomarker method for Parkinson's disease, which was previously unavailable.
Enables early detection and tracking of PD onset and progression or severity, including monitoring during therapeutic interventions.
Facilitates improved sensitivity (90%) and specificity (80%) in distinguishing PD patients from healthy controls compared to previous approaches.
Allows for more objective and accessible monitoring of PD patients over time, potentially outperforming clinical symptom assessments.
Documented Applications
Diagnosis of Parkinson's disease in human subjects using blood biomarkers.
Prognosis and monitoring of disease progression in Parkinson's disease patients through serial measurement of blood gene expression.
Treatment decision support for human subjects diagnosed with Parkinson's disease based on molecular diagnostic results.
Use of primer kits in clinical laboratories to detect HNF4A and PTBP1 mRNA expression for PD diagnosis, prognosis, or monitoring.
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